Heart failure is the leading cause of death in Western countries. It has been estimated that approximately 80 million American adults (1 in 3) have one or more forms of cardiovascular disease (CVD). Long-term survival after diagnosis remains poor despite recent improvements in pharmacological and surgical therapy, and development of new forms of treatment is urgently needed. Clinical studies have suggested the potential use of cell-based therapy in the treatment of CVD. However, current clinical results are inconsistent and demonstrated modest benefits. One leading issue that requires experimental attention is poor survival of injected cells. Elucidation of the mechanisms involved in stem cell death and development of new ways to prevent it upon transplantation is essential to maximize the cardioprotective and therapeutic potential of any stem cell type. Our long-term goal is to define new ways to improve stem cell retention and engraftment in the myocardium after transplantation, what can lead to increased myocardium regeneration. One of the first steps that occur after transplantation involves cell adhesion to the tissue extracellular matrix. This interaction is mediated by proteins localized on the cell surface known as integrins. In this proposal, we will test if specific integrins can enhance cardiac stem cell attachment to the myocardium extracellular matrix when overexpressed, and improve myocardium regeneration and function. Our proposed aims will advance understanding of stem cell engraftment in ischemic myocardium and allow direct determination of the link between enhanced engraftment and functional outcome of cell therapy. Insights developed from this grant could provide a significant translational advance in the new area of cell-based therapy.